PET Imaging Tau Accumulation in FTLD and Atypical Alzheimer's Using [18F]-PI-2620

Inclusion Criteria: participants must fulfill all of the criteria for one of the following groups.

1. Group 1: cognitively and neurologically normal subjects (CN, n=25)

1. Male or female ≥ 18 years of age currently enrolled in UNICORN (IRB #842873)

2. Cognitively and neurologically normal according to one of the following criteria:

   i. Mini-Mental Status Exam (MMSE; Folstein et al., 1975) score > 27, OR ii. Montreal Cognitive Assessment (MoCA; Carson et al., 2017; Nasreddine et al., 2005) score > 25, OR iii. Global Clinical Dementia Rating of 0, OR iv. Evaluation by a trained clinician

3. Not clinically depressed, according to one of the following criteria:

   i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

4. No history of early-onset neurodegenerative disease in biological siblings or parents, based on the investigators' assessment of the participant's self-reported history.

2. Group 2: non-amnestic Alzheimer's disease (naAD, n=15)

1. Male or female ≥ 18 years of age currently enrolled in UNICORN (IRB #842873)
2. Clinically diagnosed by a trained clinician as having a non-amnestic syndrome attributed to likely AD pathology, including but not limited to logopenic-variant primary progressive aphasia (lvPPA), posterior cortical atrophy (PCA), behavioral/dysexecutive AD (bvAD), corticobasal syndrome due to AD (CBS-AD), non-amnestic mild cognitive impairment (naMCI), or non-amnestic AD (naAD).

3. Not clinically depressed, according to one of the following criteria:

   i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

4. Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.

3. Group 3: FTLD likely due to tau (FTLD-tau, n=25)

1. Male or female ≥ 18 years of age currently enrolled in UNICORN (IRB #842873)
2. Clinically diagnosed by a trained clinician as having a neurodegenerative syndrome likely due to tau , including but not limited to progressive supranuclear palsy (PSP), non-fluent agrammatic primary progressive aphasia (naPPA), corticobasal syndrome (CBS), or behavioral-variant frontotemporal dementia (bvFTD).

3. Not clinically depressed, according to one of the following criteria:

   i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

4. Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.

4. Group 4: FTLD likely due to TDP-43 (FTLD-TDP, n=12)

1. Male or female ≥ 18 years of age currently enrolled in UNICORN (IRB #842873)
2. Clinically diagnosed by a trained clinician as having a dementia syndrome associated with likely TDP-43 pathology, including but not limited to amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD) or semantic-variant primary progressive aphasia (svPPA).

3. Not clinically depressed, according to one of the following criteria:

   i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

4. Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.
5. Group 5: having a known genetic mutation associated with FTLD-tau (genetic FTLD-tau, n=12)

1. Male or female ≥ 18 years of age 2. Currently enrolled in UNICORN (IRB #842873) with a genetic test result indicating a mutation in the MAPT gene.

3. Clinically diagnosed by a trained clinician as having an appropriate neurodegenerative condition OR confirmed as an asymptomatic mutation carrier.

4. Not clinically depressed, according to one of the following criteria: i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician 5. Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.

6. Group 6: having a known genetic mutation associated with FTLD-TDP (genetic FTLD-TDP, n=3)

1. Male or female ≥ 18 years of age
2. Currently enrolled in UNICORN (IRB #842873) with a genetic test result indicating a mutation in the GRN gene or in open reading frame 72 of chromosome 9 (C9orf72).
3. Clinically diagnosed by a trained clinician as having an appropriate neurodegenerative condition OR confirmed as an asymptomatic mutation carrier.

4. Not clinically depressed, according to one of the following criteria:

   i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

5. Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.

7. Group 7: amnestic Alzheimer's disease (naAD, n=15)

1. Male or female ≥ 18 years of age currently enrolled in UNICORN (IRB #842873)
2. Clinically diagnosed by a trained clinician as having amnestic mild cognitive impairment (MCI) or amnestic Alzheimer's disease (aAD).

3. Not clinically depressed, according to one of the following criteria:

   i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

4. Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.

Exclusion Criteria for all groups: Participants will be excluded from enrollment if they meet any of the following criteria.

1. The participant has any medical or psychiatric conditions that, in the opinion of the investigator, would compromise the participant's safety or successful participation in the study.
2. The investigators of UNICORN (IRB #842873) have determined the participant has evidence of structural abnormalities such as major stroke or mass on MRI scan within \< 6 months prior to enrollment that is likely to interfere with analysis of the PET scan.
3. The participant is unable to tolerate or have a contraindication to imaging procedures in the opinion of an investigator.
4. Females who are pregnant or breast feeding at the time of the baseline PET/CT scan will not be eligible for this study. A urine pregnancy test will be performed in women of child-bearing potential at screening and within 24 hours of any scheduled PET/CT.
5. The participant has a history of significant past or ongoing alcohol abuse or substance abuse, or dependence based on medical record review or self-reported (may be excluded at the discretion of the investigator.)
6. The participant is enrolled in a clinical trial for a disease-modifying treatment that targets the molecular pathology underlying their neurodegenerative disease.